Long-term constancy of body salt content is a requirement for maintenance of body fluid volumes and arterial blood pressure, and this constancy is achieved by the renal excretion of Na in an amount that matches Na intake. Urinary Na excretion results from the filtration of plasma in the renal glomeruli and subsequent reabsorption of most of the filtered Na along the renal tubules. Defective absorption of Na and water is the cause for a number of diseases including Bartter's syndrome and pseudohypoaldosteronism. In several instances, however, symptomatic salt losses do not occur despite defective absorption of Na suggesting the operation of compensatory mechanisms. Studies in NHE3 and AQP1 knockout mice, transport proteins in the proximal tubule where 60-70% of the filtered Na is normally absorbed, have shown that these mice maintain a normal salt balance and that a reduction in glomerular filtration rate is the main compensatory mechanism preventing salt losses. The reduction in GFR is caused by a signal transmitted from the distal tubule to the glomerular arterioles across the juxtaglomerular apparatus. This mechanism, called the tubuloglomerular feedback (TGF) mechanism, is rendered inoperative by inhibition of the Na,K,2Cl-cotransporter in the loop of Henle (NKCC2). NKCC2 mutations such as in Bartter's syndrome are therefore not compensated by GFR reductions. NKCC2 mutations also result in overproduction of prostaglandins which contribute to the salt loss, a notion supported by the reduced natriuretic response to NKCC2 inhibition in cyclooxygenase knockout mice. Using micropuncture techniques in mice with a knockout of the epithelial nitric oxide synthase (bNOS) gene we identified formation of NO in the juxtaglomerular apparatus as an important regulating factor in the TGF mechanism. NO produced by endothelial NO synthase (eNOS) is mainly responsible for the low basal renal vascular resistance since renal blood flow and GFR are greatly reduced in eNOS knockout mice.